Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1.

IF 6.8 2区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS
Aliaa E Ali, Li-Li Li, Michael J Courtney, Olli T Pentikäinen, Pekka A Postila
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引用次数: 0

Abstract

De novo mutations in the synaptic GTPase activating protein (SynGAP) are associated with neurological disorders like intellectual disability, epilepsy, and autism. SynGAP is also implicated in Alzheimer's disease and cancer. Although pathogenic variants are highly penetrant in neurodevelopmental conditions, a substantial number of them are caused by missense mutations that are difficult to diagnose. Hence, in silico mutagenesis was performed for probing the missense effects within the N-terminal region of SynGAP structure. Through extensive molecular dynamics simulations, encompassing three 150-ns replicates for 211 variants, the impact of missense mutations on the protein fold was assessed. The effect of the mutations on the folding stability was also quantitatively assessed using free energy calculations. The mutations were categorized as potentially pathogenic or benign based on their structural impacts. Finally, the study introduces wild-type-SynGAP in complex with RasGTPase at the inner membrane, while considering the potential effects of mutations on these key interactions. This study provides structural perspective to the clinical assessment of SynGAP missense variants and lays the foundation for future structure-based drug discovery.

原子模拟揭示了错义突变对 SynGAP1 结构和功能的影响。
突触 GTPase 激活蛋白(SynGAP)的新突变与智力障碍、癫痫和自闭症等神经系统疾病有关。SynGAP 还与阿尔茨海默病和癌症有关。虽然致病变体在神经发育疾病中的渗透率很高,但其中有相当一部分是由难以诊断的错义突变引起的。因此,为了探究 SynGAP 结构 N 端区域的错义效应,我们进行了硅诱变。通过对 211 个变体进行 3 次 150-ns 重复的大量分子动力学模拟,评估了错义突变对蛋白质折叠的影响。还利用自由能计算定量评估了突变对折叠稳定性的影响。根据突变对结构的影响,将其分为潜在致病和良性突变。最后,研究介绍了野生型-SynGAP 在内膜上与 RasGTPase 的复合物,同时考虑了突变对这些关键相互作用的潜在影响。这项研究为 SynGAP 错义变体的临床评估提供了结构视角,并为未来基于结构的药物发现奠定了基础。
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来源期刊
Briefings in bioinformatics
Briefings in bioinformatics 生物-生化研究方法
CiteScore
13.20
自引率
13.70%
发文量
549
审稿时长
6 months
期刊介绍: Briefings in Bioinformatics is an international journal serving as a platform for researchers and educators in the life sciences. It also appeals to mathematicians, statisticians, and computer scientists applying their expertise to biological challenges. The journal focuses on reviews tailored for users of databases and analytical tools in contemporary genetics, molecular and systems biology. It stands out by offering practical assistance and guidance to non-specialists in computerized methodologies. Covering a wide range from introductory concepts to specific protocols and analyses, the papers address bacterial, plant, fungal, animal, and human data. The journal's detailed subject areas include genetic studies of phenotypes and genotypes, mapping, DNA sequencing, expression profiling, gene expression studies, microarrays, alignment methods, protein profiles and HMMs, lipids, metabolic and signaling pathways, structure determination and function prediction, phylogenetic studies, and education and training.
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